Research over the past 25 years has led to the understanding that erectile function is an integrated vascular process that is dependent on interactions between the vascular endothelium, nerves and cavernosal smooth muscle;with nitric oxide (NO) the principal mediator of this process. Erectile dysfunction (ED) is a major health care problem that afflicts some 30 million men in the US and this number is expected to double within the decade. Hypercholesterolemia is one of the strongest risk factors for the development of ED. Therefore, in most men with ED, the underlying pathophysiology is a non-traumatic, injury to the vascular bed that impairs endothelial and vascular smooth muscle cell function within penile tissue. Phosphodiesterase (PDE) 5 inhibitors provide treatment options for patients with ED but do not reverse the vascular injury. Angiogenesis is the growth and proliferation of endothelial cells from existing vascular structures and several angiogenic growth factors, including vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), are present in corporal tissue. The central hypothesis in the initial funding period for DK62997 was that angiogenic growth factors could induce structural and functional benefits in rabbit corporal tissue in the setting of diet-induced hypercholesterolemia. Though an number of major findings were made and reported work performed during this same period has also showed that the effects of VEGF and bFGF were highly dose and route dependent, and local and/or systemic toxicity could readily occur with these agents. Following injury or angiogenic therapy, a directional association between changes in VEGF ligand and VEGF receptor signaling in corporal tissue was found;but association is not causality. Targeting individual cells types within the complex corporal vascular structure is now feasible. In this revised application, we will test the central hypothesis that a loss of VEGF receptor-ligand signaling within the corpus cavernosum is both the mechanism for hypercholesterolemia induced ED as well as a target for therapeutic strategies designed to prevent and reverse ED. To that end, the specific aims are: I: Establish that a loss of VEGF ligand-mediated receptor signaling within the corpus cavernosum is sufficient to recapitulate the vascular abnormalities that are caused by hypercholesterolemia induced ED. II: Establish whether modulation of VEGF signaling, within corporal endothelial cells, is sufficient to prevent/limit the induction hypercholesterolemia induced vascular injury. III: When a major end-product of the VEGFR/PI3-kinase-Akt pathway is absent, determine the potential mechanisms of, as well the vulnerability to, hypercholesterolemia induced vascular injury in corporal tissue. IV: Establish that in the setting of established hypercholesterolemia induced vascular injury modulation of the VEGF receptor-ligand family within endothelium is able to reverse abnormalities in vascular smooth muscle and erectile dysfunction. Research over the past 25 years has led to the understanding that erectile function is a complex and integrated vascular process that is dependent on interactions between many different cells and nitric oxide (NO) the principal mediator of this process. Erectile dysfunction (ED) is a major health care that afflicts millions of men in the United States. In a very large number of patients with ED, the underlying problem is a non-traumatic vascular injury that impairs the endothelial and vascular smooth muscle cell interactions in penile tissue. This project was funded 4 years ago to test the central hypothesis that angiogenic growth factors could induce structural and functional benefits in rabbit corporal tissue in the setting of diet-induced hypercholesterolemia. A number of findings were made and published. In this renewal, we propose to identify the mechanism for hypercholesterolemia induced vascular injury as well as how to employ information gained in the studies to advance potential treatments for ED.